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Toxicokinetics is the study of the drug movement around the body (Absorption, Distribution, metabolism, and Elimination)
Toxicokinetic data is best derived using radio labeled dose of the drug. This allows for following the fate of the drug , metabolic products, distribution in the tissue, storage sites, as well as its elimination.
Unfortunately, these methods do not provide knowledge about proportion of the drug left intact to its metabolites.
TK is concerned with what the body does to the toxicant.

Absorption
Ingestion
Inhalation
Skin penetration
Parenteral
Non-compartment
Zero
First
Order of reaction
Compartment
Physiological-based TK
Quantitative model
Distribution
Circulation
Adipose tissue
Highly perfused ogan
Blood-brain barrier
Clearance
Half-life
Volume of distribution
Bioavailability
Parameters
Toxicokinetics
Metabolism
Phase 1
Phase 2
Active
Passive
Membrane transportation
Excretion
Kidney
Lung
Feces
Saliva
Lactation
Sweating

 Toxicodynamics is the study of toxic actions of xenobiotic substances on living systems.
 Toxicodynamics is concerned with processes and changes that occur to the drug at the target tissue, including metabolism and binding that results in an adverse effect.
 Simply, TD is concerned with what the toxicant do to the body

Dosage
Exposure
Plasma
Conc.
Site of action
Toxic
Effects
Toxicokinetics Toxicodynamics

xenobiotic
ABSORPTION
EXTERNAL
MEMBRANE
BARRIERS skin
G.I. tract lungs
DISTRIBUTION
BLOOD PLASMA
TISSUES depots
METABOLISM
PHASE-1
PHASE-2
EXCRETION
KIDNEYS
LIVER lungs saliva sweat breast milk

Ingestion
Gastrointestinal trac t
Inhalation Intravenous
Lung
Intraperitoneal
Subcutaneous
Intramusc ular absorption
Dermal
Liver
Blood and lymph
Bile ex tracellular fluid fat distribution body organs Kidney Lung
Secretory
Structures soft tis sue bone
Bladder Alveoli excretion feces Urine Expired Air Secretions

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1.
2.
3.
Toxicokinetics study four processes:
Absorption
Distribution
Metabolism
4.
Excretion
Metabolism and excretion processes are combined as a single process called elimination

The toxicokinetics of a chemical are determined by measuring the concentrations of the chemical in plasma (usually) or blood at various times following a single dose. The fundamental parameters that define the rates and extents of distribution and elimination are derived from data following an intravenous or oral dose.

1.
2.
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The effect which a drug produces is dependent on:
The dose
The concentration in the target organ
The kinetics of a drug may differ from therapeutic dose to its toxic dose
Toxicokinetics is important in predicting the plasma concentration of a drug

Toxicity depends on:
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Duration and concentration of drug at the portal of entry
The rate and amount (extent) of drug absorbed ; toxicity will be low at slow absorption rates. This means that a highly toxic drug that is poorly absorbed may have same hazard as another with low toxicity but is highly absorbed.
The distribution of drug within the body ; where most drugs are distributed in highly perfused organs like brain, liver and kidneys. However, in some cases, the organ in which the drug is concentrated may not necessarily suffer the damage. An example is organochlorine compounds concentrated in adipose tissue while the target organ is the brain.

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The efficiency of biotransformation and nature of metabolites ; where, in some cases, a drug may be transformed to a more toxic metabolite or a more lipid soluble or water soluble metabolite, which affects absorption and distribution
The ability of the drug to pass through cell membranes and interact with cell constituents .
Example, some organochlorines affect the DNA
The amount and storage duration of the drug or its metabolites in the tissue . These may induce toxicity after a long time after exposure. Lead in bones is an example
The rate and site of excretion ; where the more rapid the excretion, the less toxicity it will produce

The term absorption describes the process of the transfer of the parent chemical from the site of administration into the general circulation, and applies whenever the chemical is administered via an extravascular route ( i.e. not by direct intravascular injection).
Many chemicals will be metabolized or transformed during their passage from the site of administration into the general circulation, so that little parent chemical may reach the general circulation , this raises the possibility of confusion in discussing the
‘ extent of absorption
’ depending on whether the data refer to the parent chemical, or to metabolites or both (when radiolabeling is used). This confusion is resolved by the proper use of the term bioavailability (the fraction of the dose administered that reaches the general circulation as the parent compound) to describe the extent of absorption.

1.
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Passive transport
This can occur by simple diffusion due to concentration gradient or
By passage of drugs through the pores (of the kidney and capillaries), i.e. by filtration
Passive transport is affected by:
 Ability of the drug to dissolve in the lipid portion of the cell membrane
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The size of the drug, in case it is water soluble. Aqueous pores are about 4A o which will allow drugs of 100-200 amu to pass
Presence of the drug in its nonionized form

• Uncharged molecules may diffuse along conc. gradient until equilibrium is reached
• No substrate specificity
• Small MW < 0.4 nm (e.g. CO, N
2
0,
HCN) can move through cell pores
• Lipophilic chemicals may diffuse through the lipid bilayer

First order rate diffusion, depends on
• Concentration gradient
• Surface area (alveoli  25 x body surface)
• Thickness
• Lipid solubility & ionization
• Molecular size (membrane pore size = 4-40 A, allowing MW of 100-70,000 to pass through)

Flicks ’s law and Diffusion dD/dt = KA (C o
- C i
) / t
Where; t dD/dt = rate of mass transfer across the membrane
K = constant (coefficient of permeability)
A
C
0
= Cross sectional area of membrane exposed to the compound
= Concentration of the toxicant outside the membrane
C i
= Concentration of the toxicant inside the membrane
= Thickness of the membrane

2. Special transport
Two types of special transport mechanisms can be identified:
1.
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Active diffusion :
Independent of or against conc. gradient
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Require energy
Substrate
– specific
Rate limited by no. of carriers
Example: Ca-pump (Ca 2+ -ATPase)

2. Facilitated diffusion : Occurs when a drug has a specific carrier protein, and does not occur against concentration gradient
 Carried by trans-membrane carrier along concentration gradient
 Energy independent
 May enhance transport up to 50,000 folds
 Example: Calmodulin for facilitated transport of Ca 2+

3. Additional transport : occurs by endocytosis; where :
 Phagocytes (cell eating) engulf the solid large particles suspended in the intracellular fluid
 Pinocytes (cell drinking) in which very small suspended particles or liquids are engulfed

1. Types of cells at the specific site:
An example is the sublingual cells which are highly vascularized which allows for rapid absorption
2. Period of time that drugs remain at the site:
Drugs are poorly absorbed within the mouth because the time a drug spends in the mouth is very short, while high absorption can occur in the intestine due to the long time a drug spends there

3. pH
This factor affects the ionizability of the drug.
The acidic nature of the fluid in the stomach facilitates the absorption of weakly acidic drugs, while both weakly acidic and basic drugs are well absorbed in the small intestine since the pH there is almost neutral
4. The concentration at the absorption site
5. Presence of food or binding substances:
These will decrease the concentration of the free drug and thus will lower its absorption

6. Rate of gastric emptying:
As emptying rate is decreased, absorption in the stomach will increase
7. Gastrointestinal motility:
This will decrease the amount absorbed in the stomach while increase the amount absorbed in the intestine
8. Absorbing surface area of the intestine
9. Blood flow to the site
10. Intestinal bacteria and gastrointestinal enzyme level
11. General condition of the patient:
Comatose decrease motility thus affecting absorption
12. Drug formulation: whether it is a slow release or other form

1.
Solubility of the drug in the blood
2.
Particle size
Large particles are deposited in the nasal tract > 5 microns; 2-5 micron particles are deposited mainly in the tracheabronchial region; while particles less than 1 micron penetrate into the alveolar sacs and absorbed into the blood
3. Water solubility
High water solubility volatile drugs are absorbed in the nasal tract; while low water solubility drugs will reach the bronchioles to alveoli

trachea
bronchial tree
• diffusion distance: ~20 mm
• total gas exchange area: ~80 m 2

trachea
Airway anatomy alveoli capillaries bronchial tree
• diffusion distance blood/air: ~20 mm
• total exchange gas exchange area: ~80 m 2

1. Condition of the skin: Stratum corneum serves as the main barrier. When abraded, increased absorption will result
2. Skin permeability coefficient
This represents the rate at which a particular drug penetrates the skin
3. Body region
Not all regions of the body have the same skin thickness.
Forehead versus palm
4. Lipid solubility
The more lipid soluble the drug is the more it will be absorbed
5. Skin hydration

The rate of absorption may be of toxicological importance because it is a major determinant of the peak plasma concentration and, therefore, the likelihood of acute toxic effects. Transfer of chemicals from the gut lumen, lungs, or skin into the general circulation involves movement across cell membranes, and simple passive diffusion of the unionized molecule down a concentration gradient is the most important mechanism . Lipid-soluble molecules tend to cross cell membranes easily and are absorbed more rapidly than water-soluble ones. The gut wall and lungs provide a large and permeable surface area and allow rapid absorption; in contrast the skin is relatively impermeable and even highly lipidsoluble chemicals can enter only slowly

The lipid solubility and rate of absorption depend on the extent of ionization of the chemical. Compounds are most absorbed from regions of the gastrointestinal tract at which they are least ionized. Weak bases are not absorbed from the stomach, but are absorbed from the duodenum which has a higher pH, whereas weak acids are absorbed from the stomach. The rate of absorption can be affected by the vehicle in which the compound is given, because rapid absorption requires the establishment of a molecular solution of the chemical in the gut lumen. Extremely lipid soluble compounds, such as dioxins, may be only partially absorbed, because they do not form a molecular solution in the aqueous phase of the intestinal contents.

The extent of absorption is important in determining the total body exposure or internal dose, and therefore is an important variable during chronic toxicity studies and/or chronic human exposure. The extent of absorption depends on the extent to which the chemical is transferred from the site of administration into the local tissue , and the extent to which it is metabolized or broken down by local tissues prior to reaching the general circulation. An additional variable affecting the extent of absorption is the rate of removal from the site of administration by other processes compared with the rate of absorption

Chemicals given via the gastrointestinal tract may be subject to a wide range of pH values and metabolizing enzymes in the gut lumen, gut wall, and liver before they reach the general circulation. The initial loss of chemical prior to it ever entering the blood is termed first-pass metabolism or presystemic metabolism ; it may in some cases remove up to 100% of the administered dose so that none of the parent chemical reaches the general circulation.
The intestinal lumen contains a range of hydrolytic enzymes involved in the digestion of nutrients. The gut wall can perform similar hydrolytic reactions and contains enzymes that can oxidize many drugs

FIRST PASS
EFFECT
Intestinal vs. gastric absorption

Irrespective of the reason that is responsible for the incomplete absorption of the chemical as the parent compound, it is essential that there is a parameter which defines the extent of transfer of the intact chemical from the site of administration into the general circulation. This parameter is the bioavailability , which is simply the fraction of the dose administered that reaches the general circulation as the parent compound. (The term bioavailability is perhaps the most misused of all kinetic parameters and is sometimes used incorrectly in a general sense as the amount of drug available specifically to the site of toxicity).

Extent of Absorption or Bioavailability
Dose
Destroyed in gut
Not absorbed
Destroyed by gut wall
Destroyed by liver to systemic circulation

Definition: the fraction of the administered dose reaching the systemic circulation and is thus a measure of first pass elimination for i.v.: 100% for non i.v.: ranges from 0 to 100% e.g. lidocaine bioavailability 35% due to destruction in gastric acid and liver metabolism

Liver
Liver vein
Systemic circulation
Liver artery

Plasma concentration
70
60
50 i.v. route
Bioavailability (F)
(AUC) o
(AUC) iv
40
30
20
10
0
0 2 4 oral route
6
Time (hours)
8 10

For xenobiotics taken by routes other than the iv, the extent of absorption and the bioavailability must be understood in order to determine whether a certain exposure dose will induce toxic effects or not. It will also explain why the same dose may cause toxicity by one route but not the other .

The fraction absorbed as the intact compound or bioavailability ( F ) is determined by comparison with intravenous (i.v.) dosing (where F = 1 by definition). The bioavailability can be determined from the area under the plasma concentration
– time curve (AUC) of the parent compound , or the percentage dose excreted in urine as the parent compound, i.e. for an oral dose:

Distribution is the reversible transfer of the chemical between the general circulation and the tissues. Irreversible processes such as excretion, metabolism, or covalent binding are part of elimination and do not contribute to distribution parameters. The important distribution parameters relate to the rate and extent of distribution.

1000 molecules
99.9
% bound
90.0
1 molecules free 100
100-fold increase in free pharmacologically active concentration at site of action.
NON-TOXIC TOXIC

The rate at which a chemical may enter or leave a tissue may be limited by two factors:
(i) the ability of the compound to cross cell membranes and
(ii) the blood flow to the tissues in which the chemical accumulates.
The rate of distribution of highly water-soluble compounds may be slow due to their slow transfer from plasma into body tissues such as liver and muscle; water-soluble compounds do not accumulate in adipose tissue. In contrast, very lipid-soluble chemicals may rapidly cross cell membranes but the rate of distribution may be slow because they accumulate in adipose tissue, and their overall distribution rate may be limited by blood flow to adipose tissue

The rate of distribution is indicated by the distribution rate constant, which is determined from the decrease in plasma concentrations in early time points after an intravenous dose. The rate constants refer to a mean rate of removal from the circulation and may not correlate with uptake into a specific tissue. Once an equilibrium has been reached between the general circulation and a tissue, any process which lowers the blood (plasma) concentration will cause a parallel decrease in the tissue concentration.

1.
Blood flow
Drugs are readily distributed to highly perfused tissue like brain, liver, and kidneys
2. Permeability limitations
Many drugs do not readily enter the brain due to the blood brain barrier
3. Protein binding
Acidic drugs are bound to the most abundant plasma protein (albumin); while basic drugs bind to a
-1acid glycoprotein.

4. Effect of pH
The pH of the blood or tissue affect the ionization of the drug and thus its distribution
5. Age
In old people, Protein binding and body water will decrease, thus increasing the concentration of the drug per unit time
6. Existence of storage sites:
These include: Adipose tissue, plasma proteins, liver, kidneys, and bone

The extent of tissue distribution of a chemical depends on the relative affinity of the blood or plasma compared with the tissues. Highly water-soluble compounds that are unable to cross cell membranes readily are largely restricted to extracellular fluid
(about 13 L per 70 kg body weight). Water-soluble compounds capable of crossing cell membranes ( e.g. caffeine, ethanol) are largely present in total body water (about 41 L per 70 kg body weight).

Lipid-soluble compounds frequently show extensive uptake into tissues and may be present in the lipids of cell membranes and adipose tissue.
. A factor which may further complicate the plasma/tissue partitioning is that some chemicals bind reversibly to circulating proteins such as albumin (for acid molecules) and acid glycoprotein (for basic molecules).

The extent and pattern of tissue distribution can be investigated by direct measurement of tissue concentrations in animals. Tissue concentrations cannot be measured in human studies and, therefore, the extent of distribution in humans has to be determined based solely on the concentrations remaining in plasma or blood after distribution is complete.

Chemicals appear to distribute in the body as if it were a single compartment.
The magnitude of the chemical’s distribution is given by the apparent volume of distribution (V d
).

d
Volume into which a drug appears to distribute with a concentration equal to its plasma concentration after distribution is complete
V d
=
Amount of drug in body
Concentration in Plasma

when a chemical shows a more extensive reversible uptake into one or more tissues the plasma concentration will be lowered and the value V d will increase. For highly lipid-soluble chemicals, such as organochlorine pesticides, which accumulate in adipose tissue, the plasma concentration may be so low that the value of V d may be many liters for each kilogram of body weight. This is not a real volume of plasma and therefore V d of distribution.
is called the apparent volume

It is an important parameter because extensive reversible distribution into tissues, which will give a high value of V d
, is associated with a low elimination rate and a long half-life . It must be emphasized that the apparent volume of distribution simply reflects the extent to which the chemical has moved out of the site of measurement (the general circulation) into tissues, and it does not reflect uptake into any specific tissue(s).